This invention relates to novel 5-(substituted phenyl)hydantoins and to pharmaceutically acceptable salts thereof as inhibitors of aldose reductase useful as therapeutic agents for the treatment of chronic diabetic complications; and to intermediates therefor.
Despite the widespread use of insulin and of the availability of a large number of synthetic hypo-glycemic agents such as the sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide) and biguanides (e.g. phenformin), the search for improved hypoglycemic agents continues. More recently, efforts have been directed to controlling certain chronic complications of diabetes, such as diabetic cataracts, neuropathy and retinopathy. Such efforts have given rise to development of aldose reductase inhibitors, compounds which inhibit the activity of the enzyme aldose reductase which is primarily responsible for regulating reduction of aldoses to the corresponding polyols. In this way, unwanted accumulation of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, kidney and peripheral nervous cord of various diabetic subjects is prevented or reduced. References which describe aldose reductase inhibitors are U.S. Pat. No. 3,821,383--1,3-dioxo-1H-benz[d,e]-isoquinoline-2(3H)-acetic acid and related compounds; U.S. Pat. No. 4,200,642--spiro-oxazolidine-2,4-diones; U.S. Pat. Nos. 4,117,230; 4,130,714; 4,147,797; 4,210,756; 4,235,911 and 4,282,229, each of which describes certain spirohydantoins; and the concurrently filed application of Schnur, entitled "Aldose Reductase Inhibiting 5-(2-Alkoxy-3-Substituted Phenyl)Hydantoins", and identified by the U.S. Ser. No. 438,200.
U.S. Pat. No. 4,281,009 describes a series of 5,5-disubstituted hydantoins in which one substituent is a substituted phenyl group and the other an alkyl or a heterocyclic group, said compounds being useful for treatment of diseases caused by stress.
Henze et al., J. Am. Chem. Soc. 64, 522-3 (1942) describe 5-phenylhydantoin and certain 5-(mono- and di-substituted phenyl)hydantoins wherein the substituents are hydroxy, alkoxy, formyl, methyl, chloro or dimethylamino. Other 5-(substituted phenyl)hydantoins are disclosed in U.S. Pat. No. 3,410,865 and in British Patent Application No. 2,063,206A. None of these known 5-(phenyl)hydantoins are reported to be aldose reductase inhibitors or to have a thio, sulfinyl or sulfonyl substituent in the phenyl ring.